Erythropoietin is a cytokine required for red blood cell formation. Erythropoietin receptor expression is not restricted to hematopoietic cells and erythropoietin activity extends beyond blood and includes neural protection and cardiac protection demonstrated in select animal models. Using the erythropoietin receptor null mouse that develops a lethal embryonic anemia, we demonstrated that erythropoietin is required for normal endocardium and myocardium development. We also observed erythropoietin receptor expressed on skeletal muscle satellite cells. Erythropoietin stimulates myoblast proliferation and modifies expression of MyoD and myogenin transcription factors to delay cell differentiation and fusion to myotubes. Erythropoietin response is lost with down regulation of its receptor after skeletal muscle differentiation. We test the hypothesis that erythropoietin administration or up regulation of its receptor on myoblasts can contribute to muscle maintenance and/or repair in the cardiovascular and skeletal muscle systems. [unreadable] In the cardiovascular system, we found that in a mouse model for myocardial ischemia-reperfusion injury, erythropoietin administration significantly reduced infarct size. Erythropoietin receptor is expressed on endothelial and cardiac myocytes and we find that eNOS expression is required to demonstrate the cardioprotective effects of exogenous erythropoietin administration. [unreadable] Myoblast transplantation for the treatment of myopathies has the potential to retard or stop muscle degeneration. We identified erythropoietin receptor expression on primitive/early myoblasts as well as more mature myoblasts isolated from mouse skeletal muscle. Erythropoietin stimulation of primary myoblasts decreased apoptosis associated with inflammatory cytokine treatment. Forced expression of erythropoietin receptor provides further protection with erythropoietin treatment. Increased erythropoietin receptor expression in myoblasts prior to transplantation with exogenous erythropoietin treatment suggest the ability of erythropoietin treatment to increase donor cell survival. [unreadable] These studies address the role of erythropoietin in heart and skeletal muscle maintenance and repair. Experiments are designed to elucidate regulatory mechanisms that determine endogenous erythropoietin receptor expression in myogenic cells, to reveal the nature of erythropoietin myoprotection and to illustrate the potential utility of erythropoietin administration in myoblast transplantation. The ability of erythropoietin to stimulate muscle progenitor cells demonstrates the potential to activate cytokine signaling to promote cell survival, an activity that is closely linked to the presence and level of receptor expression..